Quinazolinone derivatives useful as vanilloid antagonists

ABSTRACT

The present invention relates to the use of a quinazolinone compound of the formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5  and m are as defined in the specification and in the claims, in free form or in salt form, and, where possible, in acid addition salt form, as a vanilloid.

SUMMARY

The present invention relates to the use of quinazolinone derivatives asvanilloid antagonists, to certain novel quinazolinone derivatives, toprocesses for preparing them, to their use as pharmaceuticals and topharmaceutical compositions containing them.

DETAILED DESCRIPTION

In a first aspect, the present invention relates to the use of aquinazolinone compound of the formula

wherein

-   -   R₁ is C₁-C₆alkyl, (C₁-C₆alkyl)C₁-C₆alkyl,        di-(C₁-C₆alkyl)C₁-C₆alkyl, C₃-C₆cycloalkyl, (C₁-C₆alkyl)amino or        di-(C₁-C₆alkyl)amino;    -   each R₂, independently, is halogen, C₁-C₆alkyl,        halogen-substituted C₁-C₆alkyl, hydroxyC₁-C₆alkyl, cyano or a        group —C(═O)—R_(2a), where R_(2a) is C₁-C₆alkyl;    -   R₃ is hydrogen, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        hydroxy, hydroxy-substituted C₁-C₆alkyl, C₁-C₆alkoxy,        C₃-C₆cycloalkyl, cyano, —C(═O)H, phenyl,        (C₃-C₆cycloalkyl)C₁-C₆alkoxy,        (C₁-C₆alkoxycarbonylamino)C₁-C₆alkoxy or        (C₁-C₆alkylcarbonylamino)C₁-C₆alkoxy;    -   R₄ is hydroxy, esterified hydroxy, etherified hydroxy, amino,        (C₁-C₆alkyl)amino, a group

or a group

where R_(4a) is C₁-C₆alkyl or halogen-substituted C₁-C₆alkyl, or a group

where R_(4b) is benzyl or phenylethyl;

-   -   R₅ is hydrogen or hydroxy; and    -   m is 1 or 2,        in free form or in salt form, and, where possible, in acid        addition salt form, as a vanilloid antagonist.

In a special embodiment of the first aspect, the present inventionrelates to the use of a quinazolinone compound of the formula I, wherein

-   -   R₁ is C₁-C₆alkyl, (C₁-C₆alkyl)C₁-C₆alkyl,        di-(C₁-C₆alkyl)C₁-C₆alkyl or C₃-C₆cycloalkyl;    -   each R₂, independently, is halo, C₁-C₆alkyl, tri-halo        substituted C₁-C₆alkyl, hydroxyC₁-C₆alkyl or a group

where R_(2a) is C₁-C₆alkyl;

-   -   R₃ is hydrogen, halo, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy or        (C₃-C₆cycloalkyl)C₁-C₆alkoxy;    -   R₄ is hydroxy, esterified hydroxy, etherified hydroxy, amino,        (C₁-C₆alkyl)amino, a group

or a group

where R_(4a) is C₁-C₆alkyl, or a group

where R_(4b) is benzyl or phenylethyl;

-   -   R₅ is hydrogen or hydroxy; and    -   m is 1 or 2,        in free or salt form and, where possible, in acid addition salt        form, as a vanilloid antagonist.

In a second aspect, the present invention relates to novel quinazolinonecompounds of the formula

wherein

-   -   R₁ is C₁-C₆alkyl, (C₁-C₆alkyl)C₁-C₆alkyl,        di-(C₁-C₆alkyl)C₁-C₆alkyl, C₃-C₆cycloalkyl, (C₁-C₆alkyl)amino or        di-(C₁-C₆alkyl)amino;    -   each R₂, independently, is halogen, C₁-C₆alkyl,        halogen-substituted C₁-C₆alkyl, hydroxyC₁-C₆alkyl, cyano or a        group —C(═O)—R_(2a), where R_(2a) is C₁-C₆alkyl;    -   R₃ is hydrogen, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        hydroxy, hydroxy-substituted C₁-C₆alkyl, C₁-C₆alkoxy,        C₃-C₆cycloalkyl, cyano, —C(═O)H, phenyl,        (C₃-C₆cycloalkyl)C₁-C₆alkoxy,        (C₁-C₆alkoxycarbonylamino)C₁-C₆alkoxy or        (C₁-C₆alkylcarbonylamino)C₁-C₆alkoxy;    -   R₄ is hydroxy, esterified hydroxy, etherified hydroxy, amino,        (C₁-C₆alkyl)amino, a group

or a group

where R_(4a) is C₁-C₆alkyl or halogen-substituted C₁-C₆alkyl, or a group

where R_(4b) is benzyl or phenylethyl; and

-   -   m is 1 or 2,        in free form or in salt form, and, where possible, in acid        addition salt form.

In a special embodiment of the second aspect, the present inventionrelates to novel quinazolinone compounds of the formula Ia, wherein

-   -   R₁ is C₁-C₆alkyl, (C₁-C₆alkyl)C₁-C₆alkyl,        di-(C₁-C₆alkyl)C₁-C₆alkyl or C₃-C₆cycloalkyl;    -   each R₂, independently, is halo, C₁-C₆alkyl, tri-halo        substituted C₁-C₆alkyl, hydroxyC₁-C₆alkyl or a group

where R_(2a) is C₁-C₆alkyl;

-   -   R₃ is hydrogen, halo, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy or        (C₃-C₆cycloalkyl)C₁-C₆alkoxy;    -   R₄ is hydroxy, esterified hydroxy, etherified hydroxy, amino,        (C₁-C₆alkyl)amino, a group

or a group

where R_(4a) is C₁-C₆alkyl, or a group

where R_(4b) is benzyl or phenylethyl; and

-   -   m is 1 or 2,        in free or salt form and, where possible, in acid addition salt        form.

Terms used in this specification have the following meanings:

“C₁-C₆alkyl” denotes straight-chain or branched C₁ to CB-alkyl, e.g.,methyl ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl ortert-butyl.

“C₁-C₆alkoxy” denotes straight-chain or branched C₁ to C₆-alkyl-oxy,e.g., methoxy, ethoxy, n-propoxy or isopropoxy.

“Halo” denotes halogen which may be I, Br, Cl or F.

“Esterified hydroxy” denotes acyloxy, preferably C₁-C₆alkanoyloxy, morepreferably C₁-C₄alkanoyloxy.

“Etherified hydroxy” denotes C₁-C₆alkoxy, preferably C₁-C₄alkoxy.

The quinazolinone compounds of the invention exist in free or salt formand, where possible, in acid addition salt form. The invention is to beunderstood as including the compounds of formulae (I) and (Ia) in freeor salt form and, where possible, in acid addition salt form. In thelatter connection, suitable pharmaceutically acceptable acid additionsalts for pharmaceutical use in accordance with the invention include,in particular, the hydrochloride salt.

In formulae (I) and (Ia), the following significances are preferredindependently, collectively or in any combination or sub-combination:

-   -   (a) R₁ is C₁-C₄alkyl, (C₁-C₄alkyl)C₁-C₄alkyl,        di-(C₁-C₄alkyl)C₁-C₄alkyl or cyclopropyl;    -   (b) each R₂, independently, is chloro, fluoro, C₁-C₄alkyl,        trifluoro-substituted C₁-C₄alkyl, more preferably        trifluoromethyl, C₁-C₄alkylcarbonyl, more preferably        methylcarbonyl, or hydroxyC₁-C₄alkyl, more preferably        hydroxymethyl;    -   (c) R₃ is hydrogen, chloro, bromo, C₁-C₄alkyl, hydroxy,        C₁-C₄alkoxy or (C₃-C₆cycloalkyl)C₁-C₄alkoxy; and    -   (d) R₄ is hydroxy, amino, (C₁-C₄alkyl)amino or a group

where R_(4a) is C₁-C₄alkyl.

In a third aspect, the present invention relates to processes forpreparing the compounds of formula (Ia) as depicted in the followingreaction schemes:

A. For preparing compounds of formula (Ia), where R₁ and R₂ are asdefined above, R₃ is as defined for a compound of formula I, R₄ is aminoand m is 1.

General DescriptionThe first step of Scheme A involves the condensation/cyclisation of theamide compound of formula 1 with a substituted aniline compound in thepresence of phosphorus trichloride to obtain the 7-nitro substitutedquinazolin-4-one compound of formula 2.

General Description:The second step of Scheme A involves the reduction of the 7-nitrosubstituted quinazolin-4-one compound of formula 2 with glacial aceticacid and iron powder to obtain the 7-amino substituted quinazolin-4-onecompound of formula 3.The corresponding alkylamines, amides and carbamates may be prepared bymethods described in the literature utilising a compound of formula 3.More particularly, the alkylamines may be prepared by subjecting acompound of formula 3 to reductive alkylation utilising an appropriatealdehyde or ketone. Alternatively, a compound of formula 3 may bereacted with a C₁-C₆alkyl halide. The amides may be prepared byacylating a compound of formula 3 with an appropriate acyl chloride. Thecarbamates may be prepared by reacting a compound of formula 3 with anappropriate alkylchloroformate.B. For preparing compounds of formula (Ia), where R₁ and R₂ are asdefined above, R₃ is as defined for a compound of formula I, R₄ ishydroxy and m is 1.

General Description:Scheme B involves the Sandmeyer reaction of the 7-amino substitutedquinazolin-4-one compound of formula 3 which was prepared as set forthin Scheme A, with concentrated sulphuric acid and sodium nitrite toobtain the 7-hydroxy substituted quinazolin-4-one compound of formula 4.

The starting compounds in Scheme A are known compounds which arecommercially available.

Working up the reaction mixtures according to the above processes andpurification of the compounds thus obtained may be carried out inaccordance with known procedures.

Acid addition salts may be produced from the free bases in known manner,and vice-versa.

Compounds of formulae (I) and (Ia) in optically pure form can beobtained from the corresponding racemates according to well-knownprocedures, e.g., HPLC with chiral matrix. Alternatively, optically purestarting materials can be used.

Stereoisomeric mixtures, e.g., mixtures of diastereomers, can beseparated into their corresponding isomers in a manner known per se bymeans of suitable separation methods. Diastereomeric mixtures, e.g., maybe separated into their individual diastereomers by means offractionated crystallisation, chromatography, solvent distribution andsimilar procedures. This separation may take place either at the levelof a starting compound or in a compound of formula (I) or (Ia) itself.Enantiomers may be separated through the formation of diastereomericsalts, e.g., by salt formation with an enantiomer-pure chiral acid, orby means of chromatography, e.g., by HPLC, using chromatographicsubstrates with chiral ligands.

In any additional process steps, carried out as desired, functionalgroups of the starting compounds which should not take part in thereaction may be present in unprotected form or may be protected, e.g.,by one or more of the protecting groups mentioned below. The protectinggroups are then wholly- or partly-removed according to one of themethods described there.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions. It is a characteristic of protecting groups that they lendthemselves readily, i.e., without undesired secondary reactions, toremoval, typically by solvolysis, reduction, photolysis or also byenzyme activity, e.g., under conditions analogous to physiologicalconditions, and that they are not present in the end-products. Theskilled artisan knows, or can easily establish, which protecting groupsare suitable with the reactions mentioned hereinabove and hereinafter.

The protection of such functional groups by protecting groups, theprotecting groups themselves, and their removal reactions are described,e.g., in standard reference works, such as J. F. W. McOmie, ProtectiveGroups in Organic Chemistry, Plenum Press, London and NY (1973); T. W.Greene, Protective Groups in Organic Synthesis, Wiley, NY (1981); ThePeptides; Volume 3, E. Gross and J. Meienhofer, Eds., Academic Press,London and NY (1981); Methoden der organischen Chemie (Methods oforganic chemistry), Houben Weyl, 4^(th) Edition, Volume 15/1, GeorgThieme Verlag, Stuttgart (1974); H. D. Jakubke and H. Jescheit,Aminosauren, Peptide, Proteine (Amino acids, peptides, proteins), VerlagChemie, Weinheim, Deerfield Beach, and Basel (1982); and Jochen Lehmann,Chemie der Kohlenhydrate: Monosaccharide und Derivate (Chemistry ofcarbohydrates: monosaccharides and derivatives), Georg Thieme Verlag.,Stuttgart (1974).

All process steps described herein can be carried out under knownreaction conditions, preferably under those specifically mentioned, inthe absence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralizing agents, e.g., ion exchangers, typically cation exchangers,e.g., in the H⁺ form, depending on the type of reaction and/or reactantsat reduced, normal or elevated temperature, e.g., in the range from−100° C. to about 190° C., preferably from about −80° C. to about 150°C., e.g., at −80° C. to 60° C., at room temperature, at −20° C. to 40°C. or at the boiling point of the solvent used, under atmosphericpressure or in a closed vessel, where appropriate under pressure, and/orin an inert atmosphere, e.g., under argon or nitrogen.

Preferred compounds of formula (I) are those wherein

-   R₁ is C₁-C₄alkyl, (C₁-C₄alkyl)C₁-C₄alkyl or C₃-C₆cycloalkyl;-   R₂ is chloro, fluoro, C₁-C₄alkyl, trifluoro-substituted C₁-C₄alkyl,    C₁-C₄alkylcarbonyl or hydroxyC₁-C₄alkyl;-   R₃ is hydrogen, chloro, bromo, C₁-C₄alkyl, hydroxy, C₁-C₄alkoxy or    (C₃-C₆cycloalkyl)C₁-C₄alkoxy;-   R₄ is hydroxy, amino or (C₁-C₄alkyl)amino;-   R₅ is hydrogen or hydroxy; and-   m is 1 or 2.

More preferred compounds of formula (I) are those wherein

-   R₁ is C₁-C₄alkyl, (C₁-C₄alkyl)C₁-C₄alkyl or C₃-C₆cycloalkyl;-   R₂ is chloro, fluoro, C₁-C₄alkyl, trifluoromethyl, methylcarbonyl or    hydroxymethyl;-   R₃ is hydrogen, chloro, bromo, C₁-C₄alkyl, hydroxy or C₁-C₄alkoxy;-   R₄ is hydroxy, amino or (C₁-C₄alkyl)amino;-   R₅ is hydrogen or hydroxy; and-   m is 1.

Preferred compounds of formula (Ia) are those wherein

-   R₁ is C₁-C₄alkyl, (C₁-C₄alkyl)C₁-C₄alkyl or C₃-C₆cycloalkyl;-   R₂ is chloro, fluoro, C₁-C₄alkyl, trifluoro-substituted C₁-C₄alkyl,    C₁-C₄alkylcarbonyl or hydroxyC₁-C₄alkyl;-   R₃ is hydrogen, chloro, bromo, C₁-C₄alkyl, hydroxy, C₁-C₄alkoxy or    (C₃-C₆cycloalkyl)C₁-C₄alkoxy;-   R₄ is hydroxy, amino or (C₁-C₄alkyl)amino; and-   m is 1 or 2.

More preferred compounds of formula (Ia) are those wherein

-   R₁ is C₁-C₄alkyl, (C₁-C₄alkyl)C₁-C₄alkyl or C₃-C₆cycloalkyl;-   R₂ is chloro, fluoro, C₁-C₄alkyl, trifluoromethyl, methylcarbonyl or    hydroxymethyl;-   R₃ is hydrogen, chloro, bromo, C₁-C₄alkyl, hydroxy, C₁-C₄alkoxy or    (C₃-C₆cycloalkyl)C₁-C₄alkoxy;-   R₄ is hydroxy, amino or (C₁-C₄alkyl)amino; and-   m is 1.

The even more preferred compounds of the formula I or Ia are thecompounds of the Examples 1 to 29, especially of the Examples 1 to 28.

Another aspect of this invention relates to the fact that the compoundsof formulae (I) and (Ia) and their pharmaceutically acceptable saltsand, where possible, pharmaceutically acceptable acid addition salts,have beneficial pharmacological activity and, therefore, are useful aspharmaceuticals. In particular, the compounds of formulae (I) and (Ia)exhibit human vanilloid antagonistic activity. More particularly, thecompounds of formulae (I) and (Ia) are active at the TRPVI receptor asdemonstrated by their ability to inhibit capsaicin and low pH activationof the TRPVI ion channel as follows:

Chinese Hamster Ovary-K1 (CHO-K1) cells, transfected to express eitherthe human, rat or guinea pig TRPV1 receptor, were grown in MinimalEssential Media (MEM) alpha medium without nucleosides supplemented withfetal calf serum (10%), 2 mM L-glutamine, 100 IU/mL penicillin, 100μg/mL streptomycin and 350-700 μg/mL geneticin. All reagents weresupplied by Invitrogen. Cells were grown in T-175 flasks or Costarblack, clear-bottomed 96-well view plates and maintained at 37° C. in a90% humidified incubator with an atmosphere of 5% CO₂ and 95% air. Thecells were passaged twice a week at a ratio of 1:10 to 1:20 to maintainsteady growth. For experimentation, cells were harvested atapproximately 80% confluency and plated onto view plates at 40,000 cellsper well in 100 μL media and grown overnight.

Calcium Mobilisation Assay

On the day of the capsaicin assay, media was aspirated and cells werewashed with 100 μL 10 mMN-2-(hydroxyethylpiperazine-N′-[2-ethane-sulfonic acid] (HEPES) bufferedHank's Balanced Salt Solution (HBSS), pH 7.4. Cells were then incubatedfor 40 minutes with 2.3 μM of the ratiometric calcium binding dyefura-2/AM (from Molecular Probes), made up in HEPES buffered HBSS,containing 0.01% pluronic F-127. For the pH assay, HEPES was omitted andthe pH of HBSS adjusted to 7.4. After washing twice with 100 μL assaybuffer, cells were incubated for 10 minutes with 100 μL of testcompounds (made up in HBSS, pH 7.4), in duplicate, at concentrationsbetween 0.001 and 30 μM. The plate was then placed in a MolecularDevices Flexstation. The TRPV1 receptor was stimulated by application ofeither capsaicin or low pH. For testing the effect of compounds forpossible antagonism, capsaicin was used at the EC₈₀ concentration whichwas 0.05 μM for the rat TRPV1 receptor, and 0.1 μM for the human andguinea pig. For pH experiments, a low pH buffered solution [60 mM2-[N-morpholino]ethane sulfonic acid (MES) in HBSS] was added to theassay wells to give a final pH of 5.5.

For determinations of antagonist IC₅₀ values (concentrations ofantagonist that inhibit responses to either pH 5.5 or capsaicin by 50%),at least 10 antagonist concentrations were measured in duplicate. Theresponse in the presence of the antagonist was calculated as apercentage of the control response to capsaicin or low pH and wasplotted against the concentration of antagonist. The IC₅₀ was estimatedby non-linear regression analysis to sigmoidal-logistic curves byActivity-Base software (v5.0.10) or Microcal Origin (v7.03). Thesevalues were averaged (means and standard error of the mean) for at leastthree independent experiments.

The compounds of formulae (I) and (Ia), e.g., the compounds of Examples1-28, show TRPVI receptor antagonist activity having IC₅₀ values in therange 0.004-30 μM.

In view of the above, the compounds of formulae (I) and (Ia) are usefulas vanilloid receptor blockers, e.g., in the treatment of diseases andconditions in which vanilloid receptor activation plays a role or isimplicated. Such conditions include, in particular, pain, e.g., bone andjoint pain (osteoarthritis), cancer pain, myofascial pain (muscularinjury, fibromyalgia) and perioperative pain (general surgery,gynecologic surgery).

The compounds of formulae (I) and (Ia) are particularly useful in thetreatment or prevention of chronic pain, especially inflammatory, e.g.,chronic inflammatory pain; inflammatory diseases, e.g., inflammatoryairways disease, e.g., chronic obstructive pulmonary disease (COPD), orin asthma; cough; urinary incontinence; migraine; visceral disorders,e.g., inflammatory bowel disease; rhinitis; cystitis, e.g. interstitialcystitis; pancreatitis; uveitis; inflammatory skin disorders; andrheumatoid arthritis.

The compounds of formulae (I) and (Ia) are thus useful as vanilloidreceptor antagonists, e.g., for the treatment of pain of various genesisor aetiology and as anti-inflammatory and/or anti-edemic agents for thetreatment of inflammatory reactions, diseases or conditions, as well asfor the treatment of allergic responses. Having regard to theiranalgesic/anti-inflammatory profile, they are useful for the treatmentof inflammatory pain, for the treatment of hyperalgesia and, inparticular, for the treatment of severe chronic pain. They are, e.g.,useful for the treatment of pain, inflammation and/or oedemaconsequential to trauma, e.g., associated with burns, sprains, fracturesor the like, subsequent to surgical intervention, e.g., aspost-operative analgesics, as well as for the treatment of inflammatorypain of diverse genesis, e.g., for the treatment of osteo and rheumatoidarthritis and rheumatic disease, teno-synovitis and gout. They arefurther suitable as analgesics for the treatment of pain associatedwith, e.g., angina, menstruation or cancer. Asantiinflammatory/anti-oedema agents, they are further useful, e.g., forthe treatment of inflammatory skin disorders, e.g., psoriasis andeczema.

As vanilloid receptor blockers, the compounds of formula (I) and (Ia)are also useful as smooth muscle relaxants, e.g., for the treatment ofspasm of the gastrointestinal tract or uterus, e.g., in the therapy ofCrohn's disease, ulcerative colitis or pancreatitis.

The compounds of formula (I) and (Ia) are in particular useful as agentsfor the therapy of airways hyperreactivity and for the treatment ofinflammatory events associated with airways disease, in particular,asthma. In addition, the agents of invention may, e.g., be used for thecontrol, restriction or reversal of airways hyperreactivity in asthma.

Inflammatory or obstructive airways diseases to which the presentinvention is applicable include asthma of whatever type or genesisincluding both intrinsic and, especially, extrinsic asthma. Thus, thecompounds of formula (I) and (Ia) are useful for the treatment ofallergic asthma, as well as, e.g., exercise induced asthma, occupationalasthma, asthma induced following bacterial infection, other non-allergicasthmas and “wheezy-infant syndrome”.

Efficacy in the treatment of asthma will be evidenced by reducedfrequency or severity of symptomatic attack, e.g., of acute asthmatic orbronchoconstrictor attack and by reduced requirement for other,symptomatic therapy, e.g., anti-inflammatory, e.g., corticosteroid; orbronchodilator, e.g., β2 adrenergic, therapy.

Inflammatory or obstructive airways diseases to which the presentinvention is applicable further include pneumoconiosis (an inflammatory,commonly occupational, disease of the lungs, frequently accompanied byrepeated inhalation of dusts) of whatever type or genesis including,e.g., aluminosis, anthracosis, asbestosis, chalicosis, ptilosis,siderosis, silicosis, tabacdsis and, in particular, byssinosis.

Further inflammatory or obstructive airways diseases and conditions forwhich the compounds of formulae (I) and (Ia) may be used include adultrespiratory distress syndrome (ARDS), chronic obstructive pulmonary orairways disease (COPD or COAD), and bronchitis. The compounds offormulae (I) and (Ia) may also be used for the treatment of allergic andvasomotor rhinitis.

In addition to the foregoing, the compounds of formulae (I) and (Ia) arealso indicated for use in the therapy of septic shock, e.g., asanti-hypovolaemic and/or anti-hypotensive agents; in the treatment ofinflammatory bowel disease; cerebral oedema; headache; migraine,inflammatory skin disease, such as eczema and psoriasis; inflammatorydisorders of the gut, e.g., irritable bowel syndrome; Crohn's disease;ulcerative colitis; and cystitis, e.g., interstitial cystitis, nephritisand uveitis.

The agents of the invention are useful in the prevention and treatmentof diseases and conditions in which human VR1 activation plays a role oris implicated, and therefore susceptible to treatment by the modulation(preferably antagonism) of VR1 receptors. Such conditions includechronic pain with an inflammatory component such as rheumatoidarthritis; bone and joint pain (osteoarthritis); post-surgical pain;musculo-skeletal pain such as fibromyalgia; myofascial pain syndromes;headache, including migraine, acute or chronic tension headache, clusterheadache, temporomandibular pain, and maxillary sinus pain; ear pain;episiotomy pain; burns, and especially primary hyperalgesia associatedtherewith; deep and visceral pain, such as heart pain, muscle pain, eyepain, orofacial pain, abdominal pain, gynaecological pain, such asdysmenorrhoea, and labour pain; pain associated with the urogenitaltract such as cystitis and vulvadynia; inflammatory skin disorders, forexample psoriasis and eczema, or itch of non-specific origin; chronicpain associated with nerve injury and/or diseases affecting the nervoussystem, such as neuropathic pain associated with post-herpeticneuralgia, diabetic neuropathy, chemotherapy-induced neuropathy,amputations (“phantom limb pain”), nerve entrapment and brachial plexusavulsions, low back pain, sciatica and ankylosing spondylitis, reflexsympathetic dystrophy and other chronic nerve injuries; complex regionalpain syndromes; central nervous system pain, such as pain due to spinalcord or brain stem damage, or stroke; gout; scar pain; pain associatedwith carcinoma, often referred to as cancer pain; respiratory diseasesincluding asthma, aluminosis, anthracosis, inflammatory airways disease,e.g. Chronic Obstructive Pulmonary Disease; chronic bronchitis,asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis,byssinosis; rhinitis including allergic rhinitis such as seasonal andperennial rhinitis, and non-allergic rhinitis; cough, either idiopathicor associated with respiratory diseases such as COPD, asthma, cysticfibrosis, cancer, or gastrointestinal disturbances such asgastro-oesophageal reflux; autoimmune diseases; gastrointestinaldisorders including but not restricted to irritable bowel syndrome,Crohn's disease, ulcerative colitis, pancreatitis, inflammatory boweldisease. Diseases of the urogenital tract, particularly cystitis;urinary incontinence including bladder detrusor hyper-reflexia andbladder hypersensitivity.

For the above-mentioned indications, the appropriate dosage will ofcourse vary depending upon, e.g., the compound employed, the host, themode of administration and the nature and severity of the conditionbeing treated. However, in general, satisfactory results in animals areindicated to be obtained at a daily dosage of from about 0.05 to about150, preferably from about 0.1 mg/kg to about 100 mg/kg animal bodyweight. In larger mammals, e.g., humans, an indicated daily dosage is inthe range from about 0.5 to about 5,000, preferably from about 1 mg toabout 500 mg of a compound of formulae (I) and (Ia), convenientlyadministered, e.g., in divided doses up to four times a day or insustained-release form.

The compounds of formulae (I) and (Ia) can be administered in vivoeither alone or in combination with other pharmaceutical agentseffective in the treatment of diseases and conditions in which vanilloidreceptor activation plays a role or is implicated includingcyclooxygenase-2 (COX-2) inhibitors, such as specific COX-2 inhibitors,e.g., celecoxib and rofecoxib; and non-steroidal anti-inflammatory drugs(NSAIDs), e.g., acetylsalicylic acid and propionic acid derivatives;tricyclic anti-depressants, e.g., Anafranil®, Asendin®, Aventyl®,Elavil®, Endep®, Norfranil®, Norpramin®, Pamelor®, Sinequan®,Surmontil®, Tipramine®, Tofranil®, Vivactil®, Tofranil-PM®;anti-convulsants, e.g., carbamazepine, oxcarbazepine and gabapentin;bradykinin B1 or B2 antagonists; and GABA_(B) agonists, e.g.,L-baclofen.

The agents of the invention can be administered in vivo either alone orin combination with other pharmaceutical agents, e.g. agents effectivein the treatment of diseases and conditions in which the human VR1activation plays a role or is implicated, such as cyclooxygenaseinhibitors, including specific COX-2 inhibitors (e.g. celecoxib,lumiracoxib, and valdecoxib) or in general nonsteroidalanti-inflammatory drugs (NSAIDs) (e.g. acetylsalicylic acid, propionicacid derivatives), anti-migraine agents such as 5-HTi agonists and CGRPantagonists, tricyclic antidepressants (e.g. clomipramine, amoxapine,nortripyline, amitriptyline, imipramine, desipramine, doxepin,trimipramine, protripyline) selective serotonic reuptake inhibitors(e.g. fluoxetine), selective noradrenaline reuptake inhibitors (e.g.duloxetine), anticonvulsants (e.g. gabapentin, pregabalin,oxcarbazepine, carbamazepine), GABA_(B) agonists (e.g. L-baclofen),opioids (e.g. morphine), CB₁ receptor agonists, bradykinin receptorantagonists, substance P antagonists.

The pharmaceutical compositions for separate administration of thecombination partners and for the administration in a fixed combination,i.e., a single galenical composition comprising at least two combinationpartners, according to the invention can be prepared in a manner knownper se and are those suitable for enteral, such as oral or rectal, andparenteral administration to mammals, including man, comprising atherapeutically effective amount of at least one pharmacologicallyactive combination partner alone or in combination with one or morepharmaceutically acceptable carriers, especially suitable for enteral orparenteral application.

Pharmaceutical compositions contain, e.g., from about 0.1% to about99.9%, preferably from about 20% to about 60%, of the activeingredients. Pharmaceutical preparations for the combination therapy forenteral or parenteral administration are, e.g., those in unit dosageforms, such as tablets including sugar-coated tablets, capsules,suppositories and ampoules. These are prepared in a manner known, perse, e.g., by means of conventional mixing, granulating, sugar-coating,dissolving or lyophilizing processes. It will be appreciated that theunit content of a combination partner contained in an individual dose ofeach dosage form need not in itself constitute an effective amount sincethe necessary effective amount can be reached by administration of aplurality of dosage units.

A further aspect of the instant invention involves the “novel”compositions comprising a pharmaceutically acceptable carrier or diluentand a therapeutically effective amount of a compound of formula (Ia), infree or salt form and, where possible, in acid addition salt form.

In accordance with the foregoing, the present invention also provides:

-   -   (1) A compound of formula (I) or (Ia) in free or salt form and,        where possible, in pharmaceutically acceptable acid addition        salt form for use as a vanilloid receptor blocker, e.g., for use        in any of the particular indications set forth hereinabove;    -   (2) A compound of formula (I) or (Ia) in free or salt form and,        where possible, in pharmaceutically acceptable acid addition        salt form for the treatment of a disease or condition in which        vanilloid receptor plays a role or is implicated;    -   (3) A method for the treatment of any of the particular        indications set forth hereinabove in a subject in need thereof        which comprises administering a therapeutically effective amount        of a compound of formula (I) or (Ia) in free or salt form and,        where possible, in pharmaceutically acceptable acid addition        salt form;    -   (4) A method for treating or preventing a disease or condition        in which vanilloid receptor plays a role or is implicated        comprising administering to a mammal in need thereof a        therapeutically effective amount of a compound of formula (I) or        (Ia) in free or salt form and, where possible, in        pharmaceutically acceptable acid addition salt form;    -   (5) Use of a compound of formula (I) or (Ia) in free or salt        form and, where possible, in pharmaceutically acceptable acid        addition salt form for the manufacture of a medicament for the        treatment or prevention of a disease or condition in which        activity of vanilloid receptor plays a role or is implicated;    -   (6) A method as set forth hereinabove comprising        co-administration, e.g., concomitantly or in sequence, of a        therapeutically effective amount of a vanilloid receptor        antagonist, e.g., a compound of formula (I) or (Ia) in free or        salt form and, where possible, in pharmaceutically acceptable        acid addition salt form and a second drug substance, said second        drug substance being, e.g., for use in any of the particular        indications set forth hereinabove; and    -   (7) A combination comprising a therapeutically effective amount        of a compound of formula (I) or (Ia) in free or salt form and,        where possible, in pharmaceutically acceptable acid addition        salt form and a second drug substance, said second drug        substance being, e.g., for use in any of the particular        indications set forth hereinabove.

In the Examples which follow, which are not intended to limit, in anyway, the scope of the present invention, the following abbreviations areused:

EtOAc ethyl acetate DCM dichloromethane

EXAMPLE 1 Preparation of7-amino-3-(4-chlorophenyl)-2-isopropyl-3H-quinazolin-4-one a)Preparation of3-(4-chlorophenyl)-2-isopropyl-7-nitro-3H-quinazolin-4-one

A suspension of 4-nitroanthranilic acid isobutyramide (4 g, 15.8 mmol),4-chloroaniline (2.2 g, 17.2 mmol) and phosphorus trichloride (5.6 mL)in toluene (150 mL) is heated to reflux (bath temperature for 150° C.)for 2 hours. The reaction mixture is allowed to cool to room temperatureand then evaporated to dryness. The residue is partitioned between waterand EtOAc and the aqueous phase is extracted (2×) with EtOAc. Thecombined organic phases are washed with water, dried (Na₂SO₄) andevaporated in vacuo. Trituration with isopropyl ether provides thedesired compound as a brown solid.

b) Preparation of the Title Compound

A mixture of the compound prepared in Example 1a above (2.4 g, 6.98mmol), iron powder (1.16 g, 20.8 mmol) and glacial acetic acid (70 mL)is stirred at 50° C. for 2.5 hours. The reaction mixture is allowed tocool to room temperature and then evaporated in vacuo to dryness. Theresidue is partitioned between water and EtOAc and the aqueous phase isextracted (2×) with EtOAc. The combined organic phases are washed withwater, dried (Na₂SO₄) and evaporated in vacuo to give a brown solid.Purification by automated flash chromatography (gradient elution:EtOAc/DCM 0-50%) provides the title compound as a pale yellow solid.

(M+H)⁺=314.2; HPLC retention time=3.9 minutes.

EXAMPLE 2 Preparation of3-(4-chlorophenyl)-7-hydroxy-2-isopropyl-3H-quinazolin-4-one

To a suspension of the compound of Example 1 (778 mg, 2.479 mmol) inconcentrated sulphuric acid/water 972 μL/1.4 mL, cooled to ice bathtemperature, is added a solution of sodium nitrite (188 mg) in water(680 μL). The mixture is stirred for 45 minutes at 0.0-5° C. (internaltemperature) and then added to sulphuric acid/water 3/2 (5 mL),pre-heated to 150° C. After stirring for 15 minutes, the mixture isallowed to cool to room temperature, filtered and extracted with EtOAc(3×). The combined EtOAc extracts are washed with water, dried (Na₂SO₄)and evaporated to a yellow-orange solid. Purification by automated flashchromatography (gradient elution: EtOAc/hexane 0-25%) provides the titlecompound as a yellow solid.

¹H NMR (400 MHz, MeOH-d₄): δ 7.91 (1H, d, J=8.7 Hz), 7.49 (2H, d, J=9.5Hz), 7.25 (2H, J=9.5 Hz), 6.93 (1H, d, J=2.3 Hz), 6.86 (1H, dd, J=2.3,8.7 Hz), 2.56 (1H, quint, J=6.7 Hz), 1.11 (6H, d, J=6.7 Hz);(M+H)⁺=315.8; HPLC retention time 4.2 minutes.

EXAMPLES 3 TO 28

The compounds of Examples 3 to 28 can be prepared in a manner analogousto that described in the previous Examples.

HPLC Retention Time (in Method of Example Structure (M + H)⁺ llminutesPreparation 3

302.0 3.5 Schemes A + B 4

356.3 5.6 Scheme A + Reductive Alkylation 5

348.2 4.3 Scheme A 6

356.3 5.5 Scheme A + Reductive Alkylation 7

370.3 6.2 Scheme A + Reductive Alkylation 8

384.3 6.7 Scheme A + Reductive Alkylation 9

448.3 6.2 Scheme A + Reductive Alkylation 10

328.2 4.3 Scheme A 11

391.7 5.4 Scheme A + Selective Halogenation 12

300.0 3.6 Schemes A + B 13

295.0 3.4 Scheme A 14

349.0 4.6 Schemes A + B 15

298.3 3.2 Scheme A 16

398.4 7.2 Scheme A + Reductive Alkylation 17

384.3 5.1 Scheme A + N-Acylation 18

329.0 5.9 Scheme A 19

297.0 3.1 Scheme A 20

313.9 4.1 Schemes A + B 21

329.0 4.6 Schemes A + B 22

350.2 5.3 Schemes A + B + Selective Halogenation 23

341.0 4.7 Scheme A 24

341.0 4.6 Schemes A + B 25

298.0 3.5 Schemes A + B 26

349.2 5.5 Scheme A + Selective Halogenation 27

394.7 5.5 Schemes A + B + Selective Halogenation 28

393.7 5.7 Scheme A + Selective Halogenation

EXAMPLE 29

The compounds 29.1 to 29.54 can be prepared in a manner analogous tothat described in the previous Examples.

HPLC Retention Time (in No. Structure minutes (M + H)⁺ 29.1

5.7 385.3 29.2

8.0 373.4 29.3

5.2 431.1 29.4

7.6 334.3 29.5

4.8 376.0 29.6

5.1 346.2 29.7

4.7 320.2 29.8

5.1 333.2 29.9

4.3 350.3 29.10

5.2 359.3 29.11

4.5 364.4 29.12

5.0 432.2 29.13

340.2 29.14

6.1 343.0 29.15

5.8 441.2 29.16

4.0 350.3 29.17

6.0 441.0 29.18

5.2 373.4 29.19

6.4 356.3 29.20

5.0 339.2 29.21

4.4 333.1 29.22

4.3 329.2 29.23

6.5 357.9 29.24

4.8 359.3 29.25

5.8 474.4 29.26

6.3 390.3 29.27

4.7 333.0 29.28

3.8 336.3 29.29

4.5 331.0 29.30

6.5 368.3 29.31

3.4 306.4 29.32

3.9 295.3 29.33

4.8 345.0 29.34

3.5 336.3 29.35

345.2 29.36

6.1 354.2 29.37

7.2 345.2 29.38

4.7 329.0 29.39

4.7 329.2 29.40

316.8 29.41

6.9 313.3 29.42

5.9 363.1 29.43

4.7 329.2 29.44

331.2 29.45

3.1 305.3 29.46

3.9 309.3 29.47

6.0 341.2 29.48

3.8 320.2 29.49

7.7 458.5 29.50

5.7 410.2 29.51

6.2 361.3 29.52

3.3 316.3 29.53

3.1 307.3 29.54

3.7 324.3

EXAMPLE 30 Preparation of Soft Gelatin Capsules

5,000 soft gelatin capsules, each comprising as active ingredient 0.05 gof one of the compounds of formula (Ia) mentioned in the precedingExamples, are prepared as follows:

Composition

Active Ingredient 250 g

Lauroglycol® 2 l

The pulverized active ingredient is suspended in Lauroglykol® (propyleneglycol laurate, Gattefossé S.A., Saint Priest, France) and ground in awet pulverizer to produce a particle size of about 1-3 μm. 0.419 gportions of the mixture are then introduced into soft gelatin capsulesusing a capsule-filling machine.

1. A compound of the formula:

in free form or in pharmaceutically acceptable salt form.
 2. Thecompound of claim 1, wherein the compound is in pharmaceuticallyacceptable salt form.
 3. A pharmaceutical composition comprising acompound of claim 1, in free form or pharmaceutically acceptable saltform, in association with a pharmaceutical carrier or diluent.
 4. Thecompound of claim 1, wherein the compound is in free form.